DESCRIPTION: (Applicant's Abstract) Cocaine abuse and dependence continue to be staggering public health problems. Despite extensive testing, there is no effective pharmacological treatment for cocaine craving and abuse. Recent data indicate that both NMDA and GABA may modulate some of cocaine's dopaminergic effects, providing new avenues for pharmacological intervention. This application requests funding for five years to conduct both controlled laboratory studies and controlled clinical pilot trials in the screening of novel medications for treating cocaine abuse and dependence. The laboratory model which will be utilized has been well-characterized and will determine the effects of each of the potential treatment medications on cocaine self-administration by non-treatment seeking, experienced cocaine users. The controlled clinical pilot trials will evaluate the same medications for their effectiveness in decreasing cocaine use in a population seeking treatment. We plan to test three agents: two NMDA antagonists, memantine and dextromethorphan, and one GABA transaminase inhibitor, vigabatrin, all with benign side effect profiles in humans. The strength of this protocol lies in our utilization of a controlled laboratory setting to examine the interactive effects of potential treatment medications with cocaine use, cocaine "craving," and cocaine's subjective and physiological effects, in addition to our utilization of controlled clinical trials, which will validate the clinical applicability of the laboratory findings.